Material to form a hydrogel

ABSTRACT

A soft film, a sponge, or a sheet in the dried state is provided, which is capable of forming a hydrogel absorbing water or blood. The film is obtainable by preparing a film-state material in the dried state from either a solution of poly(acrylic acid) or a solution of polyvinylpyrrolidone, and bringing the film-state material into contact with the other remaining solution, and then drying or freeze-drying it.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of copending application Ser. No.14/693,098, filed on Apr. 22, 2015, which is a continuation applicationfrom International Patent Application No. PCT/JP2013/078612, filed Oct.22, 2013, claiming the benefit of the conventional priority fromJapanese Patent Application No. 2012-233453, filed Oct. 23, 2012; andJapanese Patent Application No. 2013-109515, filed May 24, 2013, all ofwhich are hereby expressly incorporated by reference into the presentapplication.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to a film or sponge which can be utilizedfor an adhesion barrier or hemostatic device.

Specifically, the present invention relates to a film or sponge whichcan be provided as a soft film or sponge in the dried state, and canform a hydrogel absorbing water or blood.

2. Background Art

A hydrogel which can adhere to a bio-tissue has been widely explored tobe applied to an adhesion barrier, hemostatic device, wound coveringmaterial, or drug-release device, and some are practicalized. A film orsponge which can adhere to wet bio-tissues such as mucous membrane orserous membrane to form an adhesive gel absorbing water around is usefulas an adhesion barrier or hemostatic device

Hydrogels derived from animal protein is known, but they have the riskof infection of viruses or bovine spongiform encephalopathy, or immuneresponse to foreign proteins. To avoid such risks, crosslinked naturalpolysaccharides were also developed. However, crosslinked naturalpolysaccharides are not very flexible in the dried state, difficult infitting to a complex shape, and thus, have a difficulty in using as anadhesion barrier. There is a problem that the chemically crosslinked gelis hard to be bio-absorbed. Recently, reports about the hydrogelcomprising synthetic polymers are increasing. However, thebiocompatibility of the gels of synthetic polymers is low, and there isa problem that the preparation of them is generally complicated.

A hydrogel formed by synthetic polymers, poly(acrylic acid) andpolyvinylpyrrolidone, through hydrogen bonding is known (Eur. Polym. J.,15, 223, 1979; Eur. Polym. J., 19, 923, 1983). This hydrogel hasbiocompatibility, and easy to be prepared. Therefore, it is expected asa hydrogel which avoids the problems above. The hydrogel of poly(acrylicacid) and polyvinylpyrrolidone is formed immediately by mixing of theiraqueous solutions, but it precipitates soon forming fibrous aggregatesthrough hydrogen bonding. Therefore, there is a problem that the film orsponge to form hydrogel cannot be prepared by merely mixing the aqueoussolutions. A hard solid can be obtained by isolating and drying theaggregate. However, if the aggregate is rehydrated, it does not absorbwater and remains as a solid, and a hydrogel cannot be reproduced.

On the other hand, it was proposed to utilize the mixture ofpoly(acrylic acid) and polyvinylpyrrolidone as a material for slowrelease device (Example 1 in Japanese Patent Application Laid-open No.Sho 60-215622, and others). Slow release formulation to be a soft gel byabsorbing water, which was improved for its drug slow release behaviorby addition of cyclodextrin to the mixture of poly(acrylic acid) andpolyvinylpyrrolidone, was proposed (Japanese Patent ApplicationLaid-open No. Hei 06-40890). The suppository preparation containingpoly(acrylic acid) and polyvinylpyrrolidone was also proposed (JapanesePatent Application Laid-open No. Hei 06-40889). However, thesetechnologies are not for utilizing the hydrogel comprising poly(acrylicacid) and polyvinylpyrrolidone as a material or treatment material formedical use. Thus, in those publications, no indication nor instructionfor the technology to reproduce the hydrogel by rehydration of theisolated and dried gel is found.

PRIOR ART DOCUMENTS Patent Documents

Patent Document 1: Japanese Patent Application Laid-open No. Sho60-215622

Patent Document 2: Japanese Patent Application Laid-open No. Hei06-40890

Patent Document 3: Japanese Patent Application Laid-open No. Hei06-40889

[Non-Patent Documents]

Non-Patent Document 1: Eur. Polym. J., 15, 223, 1979

Non-Patent Document 2: Eur. Polym. J., 19, 923, 1983

SUMMARY OF THE INVENTION 1. Problems to be Solved by the Invention

The present invention has as an object to provide a film or sponge whichcan be utilized for an adhesion barrier or hemostatic device.

Specifically, the present invention has as an object to provide a filmor sponge which can be provided as a soft film or sponge in the driedstate, and can form a hydrogel absorbing water or blood.

2. Means for Solving the Problems

As mentioned above, when the aqueous solutions of poly(acrylic acid) andpolyvinylpyrrolidone are mixed, the hydrogel is formed immediately byhydrogen bonding of poly(acrylic acid) and polyvinylpyrrolidone.However, there is a problem that it precipitates soon forming fibrousaggregates through hydrophobic bonding. In addition, there is a problemthat hydrogel cannot be effectively reproduced by hydrating theaggregate which was isolated and dried.

The inventors of the present invention conducted extensive studies onthe biocompatible hydrogel obtainable from poly(acrylic acid) andpolyvinylpyrrolidone so that the hydrogel can be easily utilized as anadhesion barrier or hemostatic device. Especially, the inventors of thepresent invention intensively investigated to provide means to prepare asoft dried gel by drying the hydrogel obtained from poly(acrylic acid)and polyvinylpyrrolidone, and those to prepare the adequately hydratedhydrogel absorbing water by hydrating the gel in the dried state.

Finally, the inventors found that a soft film could be obtained bydrying either an aqueous solution of poly(acrylic acid) or that ofpolyvinylpyrrolidone so as to form a film, followed by bringing the filminto contact with the solution of the other polymer, and then dryingThey also found that the film formed a hydrogel absorbing water. Theinventors also found that when the film in the dried state was put on atissue surface or a bleeding site, it absorbed water or blood rapidly toform a gel, which was very effective in avoiding adhesion or arrestinghemorrhage. Moreover, they confirmed that the hydrogel produced from theattached film was slowly degraded and solubilized under physiologicalconditions after being attached.

The inventors of the present invention found that the soft elasticspongy solid which is obtainable by freeze-drying a mixed solution ofpoly(acrylic acid) and polyvinylpyrrolidone under the presence of awater-soluble polymer such as hyaluronic acid or a salt thereof could beutilized as the film mentioned above. Moreover, they found that a sheetlike Japanese paper could be obtained by drying either an aqueoussolution of poly(acrylic acid) or an aqueous solution ofpolyvinylpyrrolidone so as to form a film, followed by bringing the filminto contact with a solution of the other solution, and thenfreeze-drying it, and be utilized as the film or sponge mentioned above.Moreover, they found that a powder being obtained by crushing thebreakable solid which is obtainable by freeze-drying a mixed solution ofpoly(acrylic acid) and polyvinylpyrrolidone under the presence of awater-soluble polymer, and a powder which is obtainable by spray dryingthe solutions of poly(acrylic acid) and polyvinylpyrrolidone on mixingcould be utilized as the film or sponge mentioned above as a material toform a hydrogel. The present invention was achieved based on thosefindings.

Namely, the present invention provides a film to form a hydrogel,comprising poly(acrylic acid) and polyvinylpyrrolidone, wherein the filmis obtainable by preparing a film-state material in the dried state fromeither a solution of poly(acrylic acid) or a solution ofpolyvinylpyrrolidone, and bringing the film-state material into contactwith the other remaining solution, followed by being dried.

The invention mentioned above provides preferable embodiments such as:the film mentioned above which is obtainable by preparing the film-statematerial from the solution of poly(acrylic acid), and bringing thefilm-state material into contact with the solution ofpolyvinylpyrrolidone, followed by being dried; the film mentioned abovewhich is obtainable by bringing the film-state material including eitherpoly(acrylic acid) or polyvinylpyrrolidone into contact with thesolution of the other remaining polymer by dropwise addition orspraying, followed by being dried; the film mentioned above wherein thesolution(s) of poly(acrylic acid) and/or polyvinylpyrrolidone include(s)poly(vinyl alcohol); and the film mentioned above wherein the solutionsare aqueous solutions or of organic solvents, or mixed solutions ofwater and organic solvents.

Moreover, the present invention provides a method for producing a filmincluding poly(acrylic acid) and polyvinylpyrrolidone to form ahydrogel, the method comprising the steps of: preparing a film-statematerial in the dried state from either a solution of poly(acrylic acid)or a solution of polyvinylpyrrolidone; and bringing the film-statematerial into contact with the other remaining solution, followed bybeing dried.

From another aspect, the present invention provides a sponge to form ahydrogel, comprising poly(acrylic acid) and polyvinylpyrrolidone,wherein the sponge is obtainable by freeze-drying a mixed solution ofpoly(acrylic acid) and polyvinylpyrrolidone under the presence of awater-soluble polymer.

The invention mentioned above provides preferable embodiments: thesponge mentioned above, wherein the water-soluble polymer is selectedfrom polysaccharides or synthetic water-soluble polymers; the spongementioned above, wherein the water-soluble polymer ismucopolysaccharides; and the sponge mentioned above, wherein thewater-soluble polymer is hyaluronic acid or a salt thereof. In addition,the sponge which is obtainable by freeze-drying the solution beingobtained by mixing the solution of poly(acrylic acid) and the solutionof polyvinylpyrrolidone under the presence of hyaluronic acid, isprovided. As a solution, an aqueous solution is preferable.

A method for producing a sponge including poly(acrylic acid) andpolyvinylpyrrolidone to form a hydrogel is provided, the methodcomprising a step of freeze-drying a mixed solution of poly(acrylicacid) and polyvinylpyrrolidone under the presence of a water-solublepolymer.

From another aspect, the present invention provides a papyraceous sheetto foam a hydrogel, comprising poly(acrylic acid) andpolyvinylpyrrolidone, wherein the sheet is obtainable by preparing afilm-state material in the dried state from either a solution ofpoly(acrylic acid) or a solution of polyvinylpyrrolidone, and bringingthe film-state material into contact with a solution including the otherremaining polymer and a water-soluble polymer, followed by being frozenand then being freeze-dried.

The invention mentioned above provides a preferable embodiment: thepapyraceous sheet mentioned above which is obtainable by preparing thefilm-state material in the dried state from the solution of poly(acrylicacid), and bringing the film-state material into contact with a solutionincluding polyvinylpyrrolidone and hyaluronic acid, followed by beingfrozen and then being freeze-dried.

Moreover, the present invention provides a method for producing apapyraceous sheet including poly(acrylic acid) and polyvinylpyrrolidoneto form a hydrogel, the method comprising the steps of: preparing afilm-state material in the dried state from either a solution ofpoly(acrylic acid) or a solution of polyvinylpyrrolidone; and bringingthe film-state material into contact with a solution of the otherpolymer and a water-soluble polymer, followed by being frozen and thenbeing freeze-dried.

Moreover, the present invention provides a powder to form a hydrogel,comprising poly(acrylic acid) and polyvinylpyrrolidone, wherein thepowder is obtainable by drying a droplet of solutions of poly(acrylicacid) and polyvinylpyrrolidone. Preferably, the powder mentioned aboveis obtainable by spray-drying the solution mentioned above. In addition,the powder to form a hydrogel, comprising poly(acrylic acid) andpolyvinylpyrrolidone, wherein the powder is obtainable by crushing abreakable solid which is obtainable by freeze-drying the mixed solutionof poly(acrylic acid) and polyvinylpyrrolidone under the presence of awater-soluble polymer, is provided.

From another aspects, medical treatment materials comprising the film,sponge, papyraceous sheet, and powder mentioned above are provided.Examples of the medical treatment materials may include an adhesionbarrier, hemostatic device, and wound covering material.

3. Effects of the Invention

According to the present invention, a film, sponge, papyraceous sheet,and powder containing poly(acrylic acid) and polyvinylpyrrolidone, toform a hydrogel, are provided. Those film, sponge, and papyraceous sheethave adequate flexibility and can be applied to a tissue surface orbleeding site in the tightly adhered state. They form a hydrogelabsorbing water or blood, and strongly adhere to the application site toachieve treatment for avoiding adhesion or arresting hemorrhage. Thepowder mentioned above can also strongly adhere to the application siteto achieve treatment for arresting hemorrhage. Both poly(acrylic acid)and polyvinylpyrrolidone are safe synthetic polymers approved aspharmaceutical excipients, and are highly biocompatible safe materials.Therefore, the film, sponge, papyraceous sheet, and powder of thepresent invention can be safely used as a medical treatment material.The hydrogel formed is slowly degraded and solubilized underphysiological conditions after being applied, so it is safe to place itin a body as an adhesion barrier.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A film provided by the present invention is characterized in that thefilm is to form a hydrogel, contains poly(acrylic acid) andpolyvinylpyrrolidone, and is obtainable by preparing a film-statematerial in the dried state from either a solution of poly(acrylic acid)or a solution of polyvinylpyrrolidone, and bringing the film-statematerial in the dried state into contact with a solution of the otherremaining solution, and then drying it.

The molecular weight of poly(acrylic acid) is not especially limited,but it is able to use those having a number average molecular weight ofabout 1,000 to 10,000,000, or crosslinked ones in the high molecularweight gel state. The molecular weight of polyvinylpyrrolidone is notespecially limited, but it is able to use those having a number averagemolecular weight of about 1,000 to 10,000,000. Sodium salts ofpoly(acrylic acid) can be used as poly(acrylic acid) in some cases.

As a solvent to dissolve poly(acrylic acid) and polyvinylpyrrolidone, itis able to use water, organic solvents such as methanol, ethanol, andacetone, which can be mixed with water at any ratio, or organicsolvents. Preferably, it is able to use water, ethanol, or the mixtureof water and ethanol, but not limited to those.

To prepare the film provided by the present invention, first, afilm-state material is prepared from either the solution of poly(acrylicacid) or polyvinylpyrrolidone in the dried state. The concentration ofthe solution is not especially limited, but it is able to use those ofabout 0.01% to 10%, preferably about 0.1% to 1%.

The method to prepare the solid film from the solution of poly(acrylicacid) or polyvinylpyrrolidone is not especially limited, but it can beprepared by, for example, putting the solution of poly(acrylic acid) orpolyvinylpyrrolidone on a plate and extending it uniformly, and removingthe solvent by air-blowing or heating. The depth of the solution on theplate is not especially limited, but it can be selected between about 1μm and 50 mm.

The thickness of the film-state material after drying is not especiallylimited, but it is, generally, between about 0.1 μm and 5 mm. Drying canbe carried out, for example, under heating at about 50-100° C., andsometimes it is favorable to be performed under lower temperature withair-blowing or reducing pressure. A water content of the film-statematerial after drying is not especially limited, but it is, generally,between about 0.1% and 10%.

The film provided by the present invention is obtainable by the driedfilm-state material containing either poly(acrylic acid) orpolyvinylpyrrolidone into contact with the solution of the otherremaining solution, and then drying it. The concentration of the lattersolution of poly(acrylic acid) or polyvinylpyrrolidone used forcontacting is not especially limited, but it is able to use those ofabout 0.01% to 10%, preferably about 0.1% to 1%.

The methods for bringing the dried film-state material into contact withthe solution containing either poly(acrylic acid) orpolyvinylpyrrolidone are not especially limited. For example, themethods such as dropwise addition, coating, or spraying of the solutioncan be enumerated, but are not limited to those. The amount of thesolution of poly(acrylic acid) or polyvinylpyrrolidone to be used forcontacting to the dried film-state material is not especially limited;however, in some cases, it is preferable to adjust the concentration andamount of the solution so that the ratio of the repeating mole unit ofthe poly(acrylic acid) or polyvinylpyrrolidone included in the driedfilm-state material to the repeating mole unit of poly(acrylic acid) orpolyvinylpyrrolidone in the solution to be used for contacting is 0.1 to10, preferably 0.5 to 2.

Drying of the film-state material after contacting with the solutionmentioned above can be carried out, for example, under heating at50-100° C., and sometimes lower temperature is favorable to be performedwith air-blowing or reducing pressure. In the present specification, theterm of “drying” must be interpreted most widely; thus, this term meansnot only as a state with completely removal of water but also as thestate still containing some water in the way of drying process, and thisterm must not be interpreted limitedly as any meanings. The watercontent of the film provided by the present invention after drying isnot especially limited, but it is, for example, between about 0.1% and10%. The thickness of the film provided by the present invention afterdrying is not especially limited, but it is, for example, between about0.1 μm and 1 mm.

It is possible to add poly(vinyl alcohol) to the solution to prepare thefilm-state material and/or the solution to contact with the film-statematerial, and it is preferable embodiments in the present invention forpreparing the film being superior in strength. The amount of poly(vinylalcohol) to be added is not especially limited, but, for example, theratio of the repeating mole unit of poly(vinyl alcohol) to the repeatingmole unit of poly(acrylic acid) can be about 0.01 to 50, preferably 0.1to 10.

In some cases, it is favorable to add poly(vinyl alcohol) to thesolution to contact with the film-state material. For example, in somecases, it is favorable to prepare the film at the molar ratio ofpoly(acrylic acid) to polyvinylpyrrolidone about 1:1 in repeating unit,using poly(vinyl alcohol) at the repeating unit molar ratio of about 5to 20. It is favorable to add poly(ethylene glycol) to the solutionsmentioned above. In some cases, by adding poly(ethylene glycol),flexibility of the film increases, and the rates of absorbing water andswelling are improved. As poly(ethylene glycol), for example,poly(ethylene glycol) 400 or poly(ethylene glycol) 4000 can be used, butit is not limited to those.

A sponge of the present invention is characterized in that the sponge isto form a hydrogel, contains poly(acrylic acid) andpolyvinylpyrrolidone, and is obtainable by freeze-drying the mixedsolution of poly(acrylic acid) and polyvinylpyrrolidone under thepresence of a water-soluble polymer. The sponge provided by the presentinvention has flexibility, and also elasticity owing to the air involvedin the solid structure.

As a solvent to dissolve poly(acrylic acid) and polyvinylpyrrolidone, itis able to use water, the organic solvents such as methanol, ethanol,acetone, which can be mixed with water at any ratio, or organicsolvents. It is preferable to use only water for efficientfreeze-drying.

As a water-soluble polymer, water-soluble polymers other thanpoly(acrylic acid) and polyvinylpyrrolidone such as polysaccharides orsynthetic water-soluble polymers can be used. Preferably, water-solublepolymers which can be utilized as thickener can be used. For example, aspolysaccharides, the followings can be enumerated; cellulose derivativessuch as hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropylmethylcellulose, mucopolysaccharides such as hyaluronic acid,chondroitin sulfate, and natural water-soluble polysaccharides such ascarrageenan, pectin, Locust bean gum, gum guaiac, xanthan gum, Whelan,but it is not limited to those. As a synthetic water-soluble polymer, itis able to use poly(vinyl alcohol) and others. As a water-solublepolymer, it is preferable to use hyaluronic acid and its salts. Ashyaluronic acid and its salts, for example, it is preferable to usehyaluronic acid sodium salts and others. The molecular weight ofhyaluronic acid is not especially limited, but it is, in some cases,preferable to use, for example, those having a number average molecularweight of not less than 200,000. By increasing the content of hyaluronicacid, in some cases, strength of the sponge increases, and tough spongecan be prepared.

The sponge of the present invention is obtainable by preparing thesolution by mixing poly(acrylic acid) and polyvinylpyrrolidone under thepresence of a water-soluble polymer, preferably hyaluronic acid or itssalts, followed by freeze-drying the solution. Generally, the solutioncan be prepared as follows: the solution of poly(acrylic acid) orpolyvinylpyrrolidone is prepared; then, water-soluble polymer,preferably hyaluronic acid or its salts, is added; and finally, thesolution of the other polymer is added. However, the method to preparethe solution to be freeze-dried is not limited to this. Mixing of thesolution can be carried out at 0° C. to room temperature. Freeze-dryingcan be performed by conventional method. If the solution is frozen inthe mold and then freeze-dried, the sponge with a desired shape can beobtained. The water content after freeze-drying is not especiallylimited, but it is, for example, between about 0.1% and 10%. The densityof the sponge of the present invention after freeze-drying is notespecially limited, but it is, for example, between about 0.01 g/cm³-0.9g/cm³.

The concentration of poly(acrylic acid) and polyvinylpyrrolidone in thesolution to be freeze-dried is not especially limited. It can be, forexample, about 0.01% to 1%. The molar ratio of the repeating unit ofpoly(acrylic acid) to the repeating unit of polyvinylpyrrolidone in thesolution can be about 0.1 to 10, preferably 0.5 to 2. The amount ofhyaluronic acid or its salts, to be added is at the ratio of therepeating mole unit of hyaluronic acid to the repeating mole unit ofpoly(acrylic acid) or polyvinylpyrrolidone can be about 0.01 to 50,preferably 0.1 to 10. It is preferable to add hyaluronic acid or itssalts as, for example, an aqueous solution. For example, in some cases,it is favorable to prepare the sponge at the molar ratio of poly(acrylicacid) to polyvinylpyrrolidone about 1:1 in repeating unit, usingwater-soluble polymer, preferably hyaluronic acid sodium salt, at therepeating unit molar ratio of about 0.1 to 0.2.

Water-soluble polymer, preferably poly(vinyl alcohol), can be added toone or both of the solutions of poly(acrylic acid) orpolyvinylpyrrolidone. If polysaccharide is used as a water-solublepolymer, water-soluble polymer, preferably poly(vinyl alcohol), can beadded to the solutions of polysaccharide. Under this condition, theamount of water-soluble polymer, preferably poly(vinyl alcohol), is notespecially limited. It is, for example, at the ratio of the repeatingmole unit of poly(vinyl alcohol) to the repeating mole unit ofpoly(acrylic acid) can be about 0.01 to 50, preferably 0.1 to 10.

A papyraceous sheet provided by the present invention is characterizedin that the papyraceous sheet to form a hydrogel, contains poly(acrylicacid) and polyvinylpyrrolidone, and is obtainable by preparing afilm-state material from either a solution of poly(acrylic acid) or asolution of polyvinylpyrrolidone, and bringing the film-state materialinto contact with the solution including the other polymer and a watersoluble polymer, followed by frozen and then being freeze-dried. In thepresent specification, the term of “papyraceous” means a state in whichfibrous polymer gathers like a paper, having much space, and,preferably, forming an elastic solid including air. Preferably the termmeans a state like Japanese paper produced in Japan. This term must notbe interpreted limitedly as any meanings and must be interpreted mostwidely.

In the embodiment mentioned above, as a means to prepare the film-statematerial in the dried state from either a solution of poly(acrylic acid)or a solution of polyvinylpyrrolidone, an appropriate means mentionedabove can be selected. Generally, it is favorable to prepare thefilm-state material from the solution of poly(acrylic acid). A means forbringing the film-state material into contact with the solutionincluding the other remaining polymer and a water-soluble polymer can beproperly selected from the common methods such as dropwise addition,coating, or spraying. As a water-soluble polymer, the material mentionedabove can be used, and preferably hyaluronic acid can be used. It isfavorable to contact the solution with the film-state material to form auniform thin layer on its surface.

The papyraceous sheet of the present invention is prepared by freezingand then freeze-drying the film-state material that has been contactedwith the solution. From the point for efficient freezing andfreeze-drying, the solutions mentioned above, preferably, are aqueoussolutions. Freezing can be carried out, for example, at −20° C., but itis not limited to this temperature. The ratio of poly(acrylic acid),polyvinylpyrrolidone, and water-soluble polymer can be appropriatelyselected using the ratios mentioned above as reference.

A powder provided by the present invention is characterized in that thepowder is to form hydrogel, contains poly(acrylic acid) andpolyvinylpyrrolidone, and is obtainable by drying the solution ofpoly(acrylic acid) or polyvinylpyrrolidone as a droplet soon after themixing. The powder of this embodiment is obtainable by, for example,spray drying the solution mentioned above by a spray drier equipped withan appropriate nozzle. Water-soluble polymer can be added to thesolution as needed.

A powder of the another aspect is provided, the powder being to form ahydrogel, containing poly(acrylic acid) and polyvinylpyrrolidone, andbeing obtained by crushing a breakable solid obtainable by freeze-dryinga mixed solution of poly(acrylic acid) and polyvinylpyrrolidone underthe presence of water-soluble polymer. To produce the powder, thebreakable solid can be prepared by the methods mentioned above. Crushingcan be performed easily by appropriate a physically powerful effect. Thesize of the powder in the situations above is not especially limited,and can be selected as needed between several μm and several mm.

The intended use of the film, sponge, papyraceous sheet, and powderprovided by the present invention is not especially limited, and can beused as, for example, a medical treatment material. They can be suitablyused as, for example, an adhesion barrier for internal organs for asurgical operation, hemostatic device for a surgical operation orinjury, or a wound covering material as protecting or healingacceleration.

A wound is, generally, a damage with failure of the skin, and asexample, cut wound, laceration, chop wound, abrasion, crush injury,contusion; bruise, bullet wound, injuries caused by bombing, sting,impalement injury, or biting wound, and also burn or bedsore areanumerated, but it is not limited to these. It can be applied to a lightwound without failure of the skin. The film, sponge, papyraceous sheet,and powder provided by the present invention can be used as a coveringmaterial for these wounds, and simultaneously as a hemostatic device forbleeding from wound site, and also as an absorber for lymph fluid fromthe wound site.

Adhesion is a phenomena where the tissues or organs normally separatedare connected, and scar tissue is formed. It occurs, for example, aftera surgical operation in the fields of gastrointestinal division,cardiology, plastic surgery, gynecology, or ophthalmology. It occurs asadhesion between gut walls, or between gut wall and abdominal wall incases of inflammatory bowel disease. As an adhesion of internal organs,other than the adhesion occurring after a surgical operation,inflammatory bowel disease, irritable bowel syndrome, a duodenal ulcer,acute enteritis, protein-losing enteropathy, colorectal cancer,appendicitis, hemorrhagic colitis, intestinal tuberculosis, intestinalBehcet, adhesive intestinal obstruction (intestinal blockage) bydiverticulosis of colon, adhesion in the abdominal cavity by peritonealdialysis, or uterine synechia by Asherman's syndrome are enumerated, butit is not limited to these. As an adhesion barrier film, an adhesionbarrier film consisting of polysaccharides (such as hyaluronic acid)(brand name: Seprafilm) was practicalized, and the film and spongeprovided by the present invention can be used as an adhesion barrier asthe products above.

The film, sponge, papyraceous sheet, and powder provided by the presentinvention can be mixed with one or more agents such as, for example,antibiotics, antiinflammatory agent, a blood coagulating agent, ananticoagulant, a local anesthetic, a vasoconstrictor or vasodilatationagent. For example, when the film, sponge, papyraceous sheet, or powderprovided by the present invention is used as an adhesion barrier in theabdominal operation, it can be mixed with agents such as antibiotics, ablood coagulating agent, and/or antiinflammatory agent. For example,when the film, sponge, papyraceous sheet, or powder provided by thepresent invention is used as a hemostatic agent, it can be mixed withagents such as antibiotics, and also with local anesthetics as needed.

The film, sponge, papyraceous sheet, and powder provided by the presentinvention are provided as in a dried state. They can be provided asbeing retained on a support, or a film including a support, as needed.Especially, the film, sponge, papyraceous sheet, and powder provided bythe present invention can be preferably provided also as being retainedon a support, or a film including a support such as, for example, clothor nonwoven fabrics of cotton or the staple fiber, a film or foam seatof soft poly(vinyl chloride), polyethylene or polyurethane, or a gauze.The powder of the present invention can be adhered to gauze orsomething. The film, sponge, papyraceous sheet, and powder provided bythe present invention are preferably provided as a sterile conditions,and are preferably stored in a container in a sealed condition afterbeing sterilized by common methods such as gas sterilization.

EXAMPLE

The following provides a more detailed explanation of the presentinvention through examples; however, the scope of the present inventioncannot be limited by the examples in any way.

Example 1

Following materials were used in the experiments.

Poly(acrylic acid) (PAA): Carbopol (registered trademark) 940,934Lubrizol Advanced Materials Inc.; or Carbopol 934P NF Polymer,Kobayashi Perfumery Co., Ltd.

Polyvinylpyrrolidone (PVP): polyvinylpyrrolidone K30, Wako Pure ChemicalIndustries, Ltd.; or Kollidon 30, Kollidon 90F, BASF Japan Ltd.

Poly(vinyl alcohol) (PVA): polyvinyl alcohol 2800, partially hydrolysed,Wako Pure Chemical Industries, Ltd.; or polyvinyl alcohol (partiallyhydrolysed), PE-05JPS, Japan VAM & POVAL Co., Ltd.

Hyaluronic acid sodium salt (HA): derived from microorganism, NACALAITESQUE, INC.; or hyaluronic acid sodium salt of the Japanesepharmacopoeia, Kewpie Corporation, or Shiseido Co., Ltd.

Poly(ethylene glycol) 400 (PEG400): Macrogo1400, NIKKO PharmaceuticalCo., Ltd

Poly(ethylene glycol) 4000 (PEG4000): Macrogo14000, NIKKO PharmaceuticalCo., Ltd.

Popidone iodine (PVP-I): Isodine mouth wash, Meiji Seika Pharma Co.,Ltd.

Chitosan (Chitosan 10): Wako Pure Chemical Industries, Ltd.

Water-soluble chitosan (Water-soluble chitosan): Kyounokusuriya Co.,Ltd.

(a) Preparation of PAA/PVP Film

Aqueous or ethanol solution of PAA (940 or 934) (0.5%, 100 μL) was castonto the substrate of polystyrene, polypropylene, or polyethylene, andwas dried at 75° C. to afford a PAA film. After drying, aqueous PVP(K30) solution (0.77%, 100 μL) was added dropwise to the surface of thePAA film, and was dried at 75° C. Mixing ratio was set to PAA:PVP=1:1 inthe repeating unit mole ratio.

(b) Preparation of PAA/PVP/PVA Film (1)

Aqueous or ethanol solution of PAA (940 or 934) (0.5%, 100 μL) was castonto the substrate of polystyrene, polypropylene, or polyethylene, andwas dried at 75° C. After drying, the mixture of the aqueous PVP (K30)solution (0.77%, 100 μL) and aqueous PVA solution (3.06%, 1-100 μL) wasadded dropwise to the surface of the PAA film, and was dried at 75° C.Mixing ratio was set to PAA:PVP:PVA=1:1:0.1-10 in the repeating unitmole ratio.

(c) Preparation of PAA/PVP/PVA Film (2)

The mixture of the aqueous solution of PAA (940 or 934) (0.5%, 100 μL)and aqueous PVA solution (3.06%, 0.5 -50 μL) was cast onto the substrateof polystyrene, polypropylene, or polyethylene, and was dried at 75° C.After drying, the mixture of the aqueous PVP (K30) solution (0.77%, 100μL) and aqueous PVA solution (3.06%, 0.5-50 μL) was added dropwise tothe surface of the PAA film, and was dried at 75° C. Mixing ratio wasset to PAA:PVP:PVA=1:1:0.1-10 in the repeating unit mole ratio.

(d) Preparation of PAA/PVP/HA Sponge (1)

To the mixed solution of aqueous PAA (934) solution (0.05%, 1 mL) andaqueous HA solution (0.04%, 1 mL) was added PVP (K30) solution (0.077%,1 mL)). It was frozen at −80° C., and then freeze-dried at roomtemperature to afford a sponge. Mixing ratio was set toPAA:PVP:HA=1:1:0.14 in the repeating unit mole ratio.

(e) Preparation of PAA/PVP/PVA Film (3)

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C.After drying, the mixture of the ethanol solution of PVP (Kollidone 30or 90F) (7.7%, 100 μL) and aqueous PVA solution (3.06%, 100-400 μL) wasadded dropwise to the surface of the PAA/PVA film, and was dried at 75°C. Mixing ratio was set to PAA:PVP:PVA=1:1:2-5 in the repeating unitmole ratio.

(f) Preparation of PAA/PVP/HA Sponge (2)

To the mixed solution of aqueous PAA (934P NF) solution (0.05%, 1 mL)and aqueous HA solution (0.04%, 1-5 mL) was added PVP ((Kollidone 30 or90F) solution (0.077%, 1 mL)). It was frozen at between −20° C. and −80°C., and then freeze-dried at room temperature to afford a sponge. Mixingratio was set to PAA:PVP:HA=1:1:0.14-0.7 in the repeating unit moleratio.

(g) Preparation of PAA/PVP//PVA/PEG Film

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C. toafford a PAA/PVA film. After drying, the mixture of the ethanol solutionof PVP (Kollidone 30 or 90F) (7.7%, 100 μL), aqueous PVA solution(3.06%, 200 μL), and ethanol solution of PEG400 or PEG4000 (3.06%,100-500 μL) was added dropwise to the surface of the PAA/PVA film, andwas dried at 75° C. to afford a soft transparent film.

(h) Preparation of PAA/PVP/PVA Film Containing Chitosan

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C. toafford a PAA/PVA film. After drying, the mixture of the ethanol solutionof PVP (Kollidone 30 or 90F) (7.7%, 100 μL) and aqueous PVA solution(3.06%, 300 μL) was added dropwise to the surface of the PAA/PVA film,and was dried at 75° C. Just before the mixture was dried up completely,powder of chitosan was added to the surface, and then the mixture wasdried up completely.

(i) Preparation of PAA/PVP/PVA Film Containing Water-Soluble Chitosan

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C. toafford a PAA/PVA film. After drying, the mixture of the ethanol solutionof PVP (Kollidone 30 or 90F) (7.7%, 100 μL), aqueous PVA solution(3.06%, 300 μL) and aqueous solution of water-soluble chitosan (1%, 100μL) was added dropwise to the surface of the PAA/PVA film, and was driedat 75° C. to afford the PAA/PVP/PVA film containing water-solublechitosan.

(j) Preparation of PAA/PVP/PVA/PEG Film Containing Water-SolubleChitosan

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C. toafford a PAA/PVA film. After drying, the mixture of the ethanol solutionof PVP (Kollidone 30 or 90F) (7.7%, 100 μL), aqueous PVA solution(3.06%, 200μL), ethanol solution of PEG400 or PEG4000 (3.06%, 100 μL),and aqueous solution of water-soluble chitosan (1%, 100 μL) was addeddropwise to the surface of the PAA/PVA film, and was dried at 75° C. toafford the flexible PAA/PVP/PVA/PEG film containing water-solublechitosan.

(k) Preparation of Water-Soluble Chitosan/PAA/PVP/PVA Film (1)

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C. toafford a PAA/PVA film. After drying, the mixture of the ethanol solutionof PVP (Kollidone 30 or 90F) (7.7%, 100 μL) and aqueous PVA solution(3.06%, 300μL) was added to the surface of the PAA/PVP film and wasdried at 75° C. After drying, solution of water-soluble chitosan (1% in50% ethanol, 500 μL) was added dropwise to the PAA/PVP/PVA film, and wasdried at 75° C. to afford the water-soluble chitosan/PAA/PVP/PVA film.

(1) Preparation of Water-Soluble Chitosan/PAA/PVP/PVA Film (2)

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C. toafford a PAA/PVA film. After drying, the mixture of the ethanol solutionof PVP (Kollidone 30 or 90F) (7.7%, 100 μL) and aqueous PVA solution(3.06%, 300 μL) was added to the surface of PAA/PVP film, and was driedat 75° C. Separately, the solution of water-soluble chitosan (0.3% in50% ethanol) was cast and dried up to a chitosan film. Both films wereattached by small amount of water to afford the water-solublechitosan/PAA/PVP/PVA film.

(m) Preparation of PAA/PVP/PVA Film Containing Iodine (1)

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C. toafford a PAA/PVA film. After drying, commercially available aqueoussolution of PVP-I (100 μL), and aqueous PVA solution (3.06%, 300 μL) wasadded dropwise to the surface, and was dried at 75° C. to afford a filmhaving antibacterial activity.

(n) Preparation of PAA/PVP/PVA Film Containing Iodine (2)

The mixture of the ethanol solution of PAA (934P NF) (0.5%, 1 mL) andaqueous PVA solution (3.06%, 100 μL) was cast onto the substrate ofpolystyrene, polypropylene, or polyethylene, and was dried at 75° C. toafford a PAA/PVA film. After drying, commercially available aqueoussolution of PVP-I (10 μL), ethanol solution of PVP (Kollidone 30 or 90F)(7.7%, 90 μL) and aqueous PVA solution (3.06%, 300 μL) was addeddropwise to the surface, and was dried at 75° C. to afford a film havingantibacterial activity.

(o) Preparation of PAA/PVP/HA Sponge Containing Chitosan

To the mixed solution of aqueous PAA (934P NF) solution (0.05%, 1 mL)and aqueous HA solution (0.04%, 1 mL) was added PVP (Kollidon 30 or 90F)solution (0.077%, 1 mL) containing powder of chitosan 10 (5 mg). It wasfrozen at −20° C., and then freeze-dried at room temperature to afford asponge. Mixing ratio was set to PAA:PVP:HA=1:1:0.14 in the repeatingunit mole ratio.

(p) Preparation of PAA/PVP/HA Sponge Containing Water-Soluble Chitosan

The solution of aqueous PAA (934P NF) solution (0.05%, 1 mL), aqueous HAsolution (0.04%, 1-3 mL), and aqueous solution of PVP (Kollidon 30 or90F) (0.077%, 1 mL) were mixed. An aqueous solution of water-solublechitosan (0.05%, 1 ml) was added to the mixture. It was frozen at −20°C., and then freeze-dried at room temperature to afford a sponge. Mixingratio was set to PAA:PVP:HA=1:1:0.14-0.42 in the repeating unit moleratio.

(q) Preparation of PAA/PVP/HA/PEG Powder

To the mixed solution of aqueous PAA (934P NF) solution (0.05%, 1 mL)and aqueous HA solution (0.04%, 1 mL) were added PVP (Kollidon 30 or90F) solution (0.077%, 1 mL) and aqueous solution of PEG400 or PEG4000(0.0306%-0.153%, 1 mL). It was frozen at −80° C., freeze-dried at roomtemperature, and then crashed by stirring to afford a powder ofPAA/PVP/HA/PEG.

(r) Preparation of PAA/PVP Powder

Aqueous solution of PAA (934P NF) (0.05%) and aqueous solution of PVP(Kollidon 30) were mixed and simultaneously spray-dried by thespray-drier equipped with a four-stream nozzle (Fujisaki Electric Co.,Ltd.) to afford PAA/PVP powder.

(s) Preparation of PAA/PVP/HA Papyraceous Sheet

The ethanol solution of PAA (934P NF) (0.5%, 1 mL) was cast onto thesubstrate of polystyrene, polypropylene, or polyethylene, and was driedat 75° C. After drying, the mixture of the aqueous solution of HA (0.4%,0-1 mL) and aqueous solution of PVP (Kollidone 30 or 90F) (0.77%, 1 mL)was added dropwise to the surface of dried PAA film. It was frozen at−20° C., and then freeze-dried at room temperature to afford apapyraceous sheet. Mixing ratio was set to PAA:PVP:HA=1:1:0-0.14 in therepeating unit mole ratio.

(t) Preparation of PAA/PVP/HA Papyraceous Sheet Attached to Gauze

The ethanol solution of PAA (934P NF) (0.5%, 1 mL) was cast onto thesubstrate of polystyrene, polypropylene, or polyethylene, and was driedat 75° C. After drying, the mixture of the aqueous solution of HA (0.4%,0-1 mL) and aqueous solution of PVP (Kollidone 30 or 90F) (0.77%, 1 mL)was added dropwise to the surface of dried PAA film. It was frozen at−20° C., and then gauze moistened by water was put on the upper surfaceor bottom surface. It was freeze-dried at room temperature to afford apapyraceous sheet attached to gauze. Mixing ratio was set toPAA:PVP:HA=1:1:0-0.14 in the repeating unit mole ratio.

(u) Preparation of Overlaid Film

Two to five films or papyraceous sheets mentioned above were bonded by asmall amount of water or aqueous solutions of water-soluble polymers,and then dried to afford film or papyraceous sheets of the overlaidstructure. By bonding with film of sodium alginate or agarose, or withgauze, the film having adhesive surface on one side was obtained.

(v) Preparation of Compressed PAA/PVP/HA Sponge Attached to Gauze

To the mixed solution of aqueous PAA (934P NF) solution (0.05%, 1 mL)and aqueous HA solution (0.04%, 0-5 mL) was added PVP (Kollidon 30 or90F) solution (0.077%, 1 mL). It was added to the container of which thegauze was laid in the bottom. It was frozen at between −20° C. and −80°C., and then freeze-dried at room temperature. After freeze-drying,lightly compressing the freeze-dried product to afford a compressedPAA/PVP/HA sponge attached to gauze. Mixing ratio was set toPAA:PVP:HA=1:1:0.-0.7 in the repeating unit mole ratio.

Example 2: Evaluation of Adhesion Barrier Effect in the Adhesion-ModelMice

Mice (ddY, male, 6-8 weeks old) were anesthetized by injection ofpentobarbital. The abdomen was incised and the cecum was exposed. It wasburned with a heated spatula, and the film provided by the presentinvention (PAA:PVP:PVA=1:1:10 in the repeating unit mole ratio) was puton the burned site. The cecum was replaced in the cavity, and theabdomen was closed. After 3 days, or a week, abdomen was again incisedunder anesthesia, and the adhesion barrier effect was evaluated. As aresult, in mice without treatment by the film, the cecum stronglyadhered to other intestines or abdominal wall. On the other hand, inmice treated by the film, the film became a gel absorbing blood or lymphfluid around the burned site, and strongly adhered to the burned site,and adhesion to other intestines or abdominal wall was not observed.From these results, it was confirmed that the film provided by thepresent invention has a high adhesion barrier effect.

Example 3: Evaluation of Hemostatic Effect in Mice

Mice (ddY, male, 6-8 weeks old) were anesthetized by injection ofpentobarbital. The abdomen was incised and incision was given on theliver. The film provided by the present invention (PAA:PVP:PVA=1:1:10 inthe repeating unit mole ratio) was put on the incised site, and it wasobserved for one hour to evaluate the hemostatic effect. It wasconfirmed that the film being attached immediately became a gelabsorbing blood, and strongly adhered to the incised site, and thehemostasis was achieved effectively.

Example 4: Evaluation of Hemostatic Effect in Mice

Mice (ddY, male, 6-8 weeks old) were anesthetized by injection ofpentobarbital. The femoral vein was exposed, and cut, and the filmprovided by the present invention (PAA:PVP:PVA=1:1:10 in the repeatingunit mole ratio), or the sponge provided by the present invention(PAA:PVP:HA=1:1:1.4 in the repeating unit mole ratio) was put on theincised site. It was observed for one hour to evaluate the hemostaticeffect. As a result, the film or sponge immediately became a gelabsorbing blood, and strongly adhered to the incised site, and thehemostasis was achieved effectively.

Example 5: Evaluation of Pressure Resistance for Hemostatic Effect

The bottoms of two cylindrical plastic tubes were connected with arubber tube. After having filled the inside with water or color water,chicken skin was bound to the upper part of one tube, and a hole wasmade in the chicken skin with a needle of 21G. The film provided by thepresent invention (PAA:PVP:HA=1:1:1.4 in the repeating unit mole ratio)was put on the hole, and made it adhere to the skin. The position of thetubes was moved lengthwise to make the film be subjected to hydraulicpressure, and observed a leak of the water. The film immediately absorbswater, and strongly adhered to the chicken skin, and completelyrestrained the leak of the water up to hydraulic pressure of 30 mmHg.

Example 6: Evaluation of Hemostatic Effect in Heparinized Mice

Mice (ddY, male, 6-8 weeks old) were anesthetized by injection ofpentobarbital. The femoral vein was exposed, and cut, and the filmsprovided by the present invention mentioned in (a)-(c), (e), (g)-(n), or(u), or the sponges provided by the present invention mentioned in (d),(f), (o), (p), (s), or (t), or the powder provided by the presentinvention mentioned in (q), or (r), or the mixture of the powderprovided by the present invention mentioned in (q), or (r) and thepowder of chitosan 10, was put on the incised site. It was observed forone hour to evaluate the hemostatic effect. As a result, the film orsponge or powder immediately became a gel absorbing blood, and stronglyadhered to the incised site, and the hemostasis was achievedeffectively. Especially, in the films, sponges, and powder containingchitosan, the hemostatic effect was greatly improved.

Example 7: Evaluation of Hemostatic Effect in Clinical Study (1)

The film provided by the present invention mentioned in (c) was put onthe needle puncture site of the patients taking warfarin. The filmbecame a gel, and adhered to the puncture site, and speedy hemostasiswas achieved.

Example 8: Evaluation of Hemostatic Effect in Clinical Study (2)

After tooth extraction, the sponge provided by the present inventionmentioned in (d) was put in the socket in the patients taking warfarin.The sponge became a gel, and adhered to the applied position, and speedyhemostasis was achieved.

Additional advantages and modifications will readily occur to thoseskilled in the art. Therefore, the invention in its broader aspects isnot limited to the specific details and representative embodiments shownand described herein. Accordingly, various modifications may be madewithout departing from the spirit or scope of the general inventiveconcept as defined by the appended claims and their equivalents.

What is claimed is:
 1. A method for producing a freeze-dried sheetincluding poly(acrylic acid) and polyvinylpyrrolidone, the methodcomprising: preparing a film-state material in a dried state from eithera solution of poly(acrylic acid) or a solution of polyvinylpyrrolidone;and bringing the film-state material into contact with the otherremaining solution, followed by being frozen and then beingfreeze-dried, wherein the freeze-dried sheet forms a hydrogel havingadhesiveness to a bio-tissue when the freeze-dried sheet absorbs wateror blood.
 2. The method according to claim 1, the method comprising:preparing the film-state material in the dried state from the solutionof poly(acrylic acid); and bringing the film-state material into contactwith the solution of polyvinylpyrrolidone, followed by being frozen andthen being freeze-dried.
 3. The method according to claim 1, wherein oneof or both of the solutions of poly(acrylic acid) andpolyvinylpyrrolidone include(s) a water-soluble polymer.
 4. The methodaccording to claim 3, wherein the water-soluble polymer is selected fromthe group consisting of hydroxyethyl cellulose, carboxymethyl cellulose,hydroxypropyl methylcellulose, chondroitin sulfate, pectin, Locust beangum, gum guaic, xanthum gum, Whelan, poly(vinylalcohol), hyaluronicacid, polyethylene glycol, and chitosan.
 5. The method according toclaim 1, wherein a repeating unit molar ratio of either poly(acrylicacid) or polyvinylpyrrolidone included in the film-state material topoly(acrylic acid) or polyvinylpyrrolidone in the other remainingsolution to be used for contacting is at the range of 0.1 or more to 10or less.
 6. The method according to claim 1, wherein the freeze-driedsheet is a medical treatment material or a component thereof.
 7. Themethod according to claim 6, wherein the medical treatment material isan adhesion barrier or a hemostatic device.
 8. The method according toclaim 6, wherein the medical treatment material is a wound coveringmaterial.